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Alcoholic Hepatitis: Current Challenges and

Future Directions Nikolaos T. Pyrsopoulos, MD, PhD, MBA

Professor and Chief,

Division of Gastroenterology and Hepatology

Medical Director Liver Transplantation

Rutgers- New Jersey Medical School

University Hospital

Outline

Disease Spectrum

Risk Factors

Clinical Presentation

Diagnosis

Prognostic Factors

Treatment

• May well be the oldest form of liver injury: fermented beverages were present as early as 10,000 BC.

Approximately 2/3 of adult Americans drink some alcohol.

Alcoholic liver disease encompasses a spectrum of injury from simple steatosis to frank cirrhosis.

Excessive alcohol consumption is the thirdleading preventable cause of death in the United States.

Total recorded alcohol per capita consumption (15+), in liters of pure alcohol

Making sense of the terminology of alcohol

Standard drink: NIAAA (National Institute on Alcohol Abuse and Alcoholism) a standard drink is any drink that contains 10 grams

of pure alcohol or 0.6 fluid ounces of pure alcohol

1 standard drink is equivalent to 1 unit

1 unit = 10 grams of alcohol

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What is a Standard DrinkBeverage Strength

by VolumeSize (volume)

Amount Standard Drinks

Low Alcohol Beer

2-3% 375 ml (1can)

10 grams 1

Regular Beer 4-5% 375 ml (1 can)

14-15 grams 1.5

Red or White Table Wine

10-14% 750 ml (1 bottle)

60-80 grams 6-8

Fortified wine (port or sherry)

18% 60 ml 10 grams 1

Spirits (gin or whiskey)

38-48% 30 ml (nip)

10 grams 1

Safe parameters for alcohol ingestion:

14 units per week in women, app 2 units/day

21 units per week in men, app 3 units/day

Prevalence and Natural History

Factors that affect the development of liver injury:

a) dose, duration, and type of alcohol

b) drinking patterns,

c) sex and ethnicity,

d) associated risk factors including obesity, iron overload, concomitant infection with viral hepatitis and genetic factors

Prevalence and Natural History drink excessively and develop physical tolerance and

withdrawal: alcohol dependence

harmful use of alcohol defined by the development of negative social and

health consequences of drinking like unemployment, loss of family, organ damage, accidental injury, or death: alcohol abusers and problem drinkers

Prevalence and Natural History

The risk of cirrhosis consumption of more than 30 grams of alcohol per day (3 units/day), the highest risk is associated with consumption of more than 120 grams per day (12 units/day)

Point prevalence of cirrhosis is 1% in persons drinking 30 to 60 grams of alcohol a day (3-6 units) and up to 5.7% in those consuming 120 grams daily (12 units)

Histology

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Assessing Illness Severity

Maddrey’s Discriminant Function

MELD

Glasgow Alcoholic Hepatitis Score

ECBL

Lille model

Disease Spectrum of ALD

Normal Liver

If abstinent for 4-6 weeks 90-100% if drink more than 6 units daily

Alcoholic Hepatitis

Fatty liver

Cirrhosis

30% if continues to drink at least 4 units daily5-15% if abstinent10-35%

40% ?

Disease Spectrum of ALD

Spectrum varies from simple steatosis to cirrhosis

3 main histological stages:

fatty liver or simple steatosis

acute alcoholic hepatitis

hepatic fibrosis or cirrhosis

Disease Spectrum: Alcoholic Hepatitis (AH)

AH: True prevalence is unknown, but histologic studies of patients with ALD (alcoholic liver disease) suggest that AH may be present in as many as 10-35% of hospitalized alcoholic patients

Likelihood that AH will progress to permanent damage is increased among those who continue to abuse alcohol, amount of alcohol is unknown that leads to cirrhosis

Up to 40% of patients with severe alcoholic hepatitis die within 6 months after the onset of the clinical syndrome, appropriate diagnosis and treatment are essential

Can you get alcoholic hepatitis if you don’t have fatty liver?

Disease Spectrum: Fibrosis/Cirrhosis

Fibrosis starts in the perivenular area and is influenced by the amount of alcohol ingested

Perivenular fibrosis and deposition of fibronectin occurs in 40-60% of patients who ingest more than 60-80 grams/daily (6-8 units) for an average of 25 years

Perivenular sclerosis has been identified as a significant and independent risk factor for the progression of alcoholic liver injury to fibrosis or cirrhosis

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Clinical Presentation of Alcoholic Hepatitis

Clinical Presentation of Alcoholic Hepatitis (AH): cardinal sign is the rapid onset of jaundice

Other common signs and symptoms include:fevers, ascites, and proximal muscle loss

Patients with severe alcoholic hepatitis may have encephalopathy

Liver may be enlarged and tender

Within several weeks after discontinuation of alcohol intake, jaundice and fever may resolve, but ascites and hepatic encephalopathy may persist for months to years

Either continued jaundice or the onset of renal failure signifies a poor prognosis

Physical Exam Findings in Alcoholic Liver Disease (ALD)

No single physical finding or constellation of findings is 100% specific or sensitive for ALD

Some features may carry independent prognostic information, with the presence of specific features associated with an increased risk of mortality over one year. These include HE, presence of visible veins across the anterior abdominal wall, edema, ascites, spider nevi, and weakness.

Several centers have mentioned the presence of a hepatic bruit, but the sensitivity and specificity of this finding is uncertain

Jaundice associated with alcoholic liver

diseaseCaput medusae Portal HTN

Esophageal Varices Normal Gastro esophageal junction

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Diagnosis

Elevated AST and ALT ( rarely > 300 IU/ml) AST/ALT > 2:1 (> 80% pts) Increased GGT (70-90% pts) -independent of liver disease Leukocytosis with neutrophilia Increased MCV (80-100% pts) –due to ETOH induced

marrow toxicity, B12/folate deficiency Elevated creatinine-ominous sign (HRS) Carbohydrate deficient transferrin Elevated IgA levels Hyperbilirubinemia, coagulopathy, TCP

When to do a Liver Biopsy in ALD?

To confirm diagnosis

Exclude other causes of liver disease including primary or concomitant

Assess extent of liver damage

Ethanol induced cirrhosis

Macronodular (nodules >3cm in diameter), Brown, Non-fatty, Shrunken (<1 kg)

Alcoholic hepatitis

“Mallory bodies” Frank Burr Mallory (1862-1941)

American pathologist at the Boston City Hospital and Professor of Pathology at Harvard Medical School, after whom the Mallory body is named.

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Prognosis

Maddrey’s Discriminant Function (mDF)Model of End Stage Liver Disease (MELD)Glasgow Alcoholic Hepatitis Score (GAHS)

Prognostic Factors: MDF

Maddrey’s Discriminant Function (MDF), a disease-specific prognostic score is used to stratify a patient’s severity of illness.

Initial formula was derived in the context of clinical trials of alcoholic hepatitis, and later modified.

modified DF=4.6 (patient’s PTT-control PTT) + total bilirubin

Score of greater than 32, highest risk of dying, with a one month mortality as high as 30-50%. If also with hepatic encephalopathy, risk for death went even higher

Score of less than 32 : 17% mortality

Prognostic Tools: MELD MELD score, poor prognosis if greater than 11, but some

sources greater than 18.

If calculated MELD again one week into the hospital course and there has been a greater than 2 point change from the admission MELD, this been shown to independently predict in hospital mortality.

90 day mortality of a MELD score of 21 was found to be 20%

Prognostic Tools:Glasgow Alcoholic Hepatitis Score (GAHS)

Age (years) <50 + 1, >50 +2

WBC <15 +1, >15 +2

Urea <5 +1, >5 +2

PT ratio or INR <1.5 +1, >1.5-2.0 +2, >2 +3

Bilirubin <125 +1, 125-250 +2, >250 +3

Score of 9 or more identifies patients most at risk of death, a score of 9 or more can be used either on day 1 (admission day) or day 6-9.

The Lille score model

3.19–0.101×Age (years) +0.147×Albumin on day 0 (g/L) +0.0165×Evolution in bilirubin level (μmol/L) −0.206×Renal insufficiency −0.0065× Bilirubin on day 0 (μmol/L) −0.0096× PT (seconds) (www.lillemodel.com)

Lille score ≥ 0.45 predicts 75% mortality within 6 months in patients who have received corticosteroid therapy.

Analysis of Prognostic ToolsmDF MELD GAHS

Pros Simple

Does not require a liver biopsy

Simple

Does not require a liver biopsy

Predicts mortality at 90 days

Simple

Does not require a liver biopsy

Predicts mortality at 28/84 days when measured at days 1 and 7

Cons Doesn’t give a mortality prediction

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Upcoming Prognostic Tool

Degree of portal hypertension may be a sensitive marker of liver injury,

new proposed scoring system includes measurements of a marker of portal hypertension with asymmetric dimethylarginine and its stereoisomer to predict outcomes, sensitivity 73%, specificity of 83%, still in the works

AASLD Guidelines

Treatment

Abstinence

Corticosteroids

Pentoxyfylline

Anticytokine Therapy

Antioxidants

Nutritional Supplementation

Other agents: PTU, Colchicine, anabolic steroids

Main ongoing studies of targeted treatment for alcoholic hepatitis and alcoholic cirrhosis

Louvet, A. & Mathurin, P. (2015) Alcoholic liver disease: mechanisms of injury and targeted treatmentNat. Rev. Gastroenterol. Hepatol. doi:10.1038.nrgastro.2015.35

Treatment Strategy

After an episode of AH, no safe amount of alcohol consumption which can be recommended as AH can persist or redevelop

Need for therapy is less urgent in patients with AH who have a low risk of complications as estimated by a MDF score of <32 or GAHS score of <9. Particularly true in patients with improving bilirubin during hospitalization

Treatment: Abstinence

Abstinence: most therapeutic intervention for patients with ALD, improvement can be relatively rapid and in 66% of patients abstaining from alcohol, significant improvement was observed in 3 months

In those patients who achieve abstinence, naltrexone or acamprosate may be considered in combination with counseling to decrease the likelihood of relapse in patients with alcohol dependence/abuse

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Treatment: Steroids

Rationale for treatment:

Suppresses immune response through the mechanism of inhibiting transcription factors such as activator protein 1 (AP-1) and NF-k B

Suppresses inflammatory response by inhibiting cytokine synthesis

Treatment: Facts about Steroids

Use has been controversial

Most common steroids: prednisolone 40 mg po daily

Indications for treatment: MDF>32 in the absence of sepsis, hepatorenal syndrome, chronic hepatitis B, GI bleeding

Lack of efficacy can be determine by calculating the Lille score after 7 days of treatment

Lille score greater than 0.45 indicates a lack of response to steroids and predicts a 6 month survival rate of less than 25%.

Alcoholic hepatitis is unresponsive to steroid treatment in approximately 40% of patients: in this subgroup, pentoxyfylline has not been identified as effective

Overview of Steroids for Alcoholic Hepatitis

Benefits of Steroids Problems

Anti-inflammatory Systemic Sepsis

Reduces cytokines Tissue Viability

Prevents tissue injury Diabetogenic

Anabolic issues Inhibits liver regeneration

Short term gain No long term survival benefit

STOPAH TrialPrednisolone or Pentoxifylline for Alcoholic

Hepatitis

Treatment: Anticytokine Therapy

Cytokines implicated in ALD: IL-6, IL-10, TNF-alpha

Treatment: Infliximab and Etanercept

Type of drug:

Infiximab: monoclonal chimeric anti-TNF antibody

Etanercept: a fusion protein containing the ligand-binding portion of the human TNF receptor fused to the Fc portion of Human IgG1

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ELADELAD

Liver transplantation 2018

Clinical and biochemical suspicion of alcoholic hepatitis

Severity stratification(Maddrey’s discriminate function, MELD, ABIO, Child, Glasgow scores

Consider (transjugular if low platelet count) liver biopsy for confirmation

Intermediate and high risk Low risk

No or controlled infection Nutritional assessmentStandard supportive care

Severe Infection

Corticosteroids(Prednisone 40 mg)

Pentoxifyline(400mg three times daily for 4 weeks

Stop CorticosteroidsConsider for MARSConsider for clinical trials

4 weeks of corticosteroidsFollowed by a 2 week taper off

Lille score model at 7days<0.45>0.45

Easy Does it and smooth on the pedal!